The serosa comprises the outermost layer of the visceral structures that lie in the pleural and peritoneal cavities of the human body; it consists of a surface epithelial layer called mesothelium and is typically reinforced by irregular fibroelastic tissue or stroma. The serous cavities of the body are also lined by a single mesothelial layer of flattened cells (e.g. peritoneum, pleura, and pericardium).
When the serous or underlying vascularized layers of the human body are disrupted, either by a traumatic injury or a deliberate surgical procedure, the body mounts a complex inflammatory wound healing response to repair the defect. Initial trauma leads to increased histamine-mediated vascular permeability and bathing of the injured tissue's local environment in inflammatory exudates, resulting in traditional repair mechanisms characterized by mesothelial and fibroblast proliferation and, depending on the extent of injury, cell-mediated contraction. An early component of the spontaneous wound response is the formation of a fibrin matrix. Fibrin provides an initial structural framework necessary for mesothelial repair (also called remesothelialization) to occur via fibroblast proliferation. Under normal conditions, mesothelial repair proceeds concurrently with fibrinolysis, a component of the repair process that dissolves the fibrin matrix through the enzymatic action of plasmin. Both an inadequate blood supply and reduced tissue oxygenation are common in surgically traumatized tissue. Under these conditions, fibrinolytic activity is decreased and weak fibrinous bands, which often connect neighboring serosal surfaces, are allowed to persist under suppressed fibrinolysis. Over the 3 to 5 days following surgical injury, fibrinous bands gradually adopt and increase their cellularity, becoming organized by infiltrating fibroblasts via the deposition of collagen into strong fibrous bands, called adhesions. Adhesions predominate in a wide variety of in vivo sites (including, but not limited to, the peritoneal, pleural, and pelvic cavities) with similar mechanisms. In addition to surgical trauma, ischemia from surgical repair (grafting, suturing), the mechanical effects of handling, the presence of foreign materials (i.e. starch), inflammation-induced peritonitis, blood, and serosal drying may inhibit fibrinolysis and lead to adhesion formation.
Adhesion formation is a major complication of serosal repair following surgery, ischemia, or infection, and leads to conditions such as intestinal obstruction, severe abdominal pain, and infertility. Intraperitoneal adhesions, for example, occur in 67 to 93% of general abdominal surgeries and at an even higher rate following open gynecological pelvic surgeries. In addition to increased patient morbidity and mortality, adhesions present a significant burden to the health care system. Postoperative adhesions often require additional surgical procedures to remove obstructions and may increase the risk, cost, and complexity of future operations. Approximately 440,000 pelvic-abdominal adhesiolysis operations are performed in US each year. When adhesiolysis is performed to remove an intestinal obstruction, adhesions form again and create a new obstruction in 11 percent to 21 percent of cases. The annual cost of care for complications of post operative adhesions has been estimated to be $1.3 billion.
A detailed description of the pathogenesis and pathophysiology of post operative adhesion formation is presented elsewhere. It reveals that two main factors are required for adhesion formation: the continuous, close contact of two intraperitoneal structures (or one such structure and a denuded peritoneal mesothelium) as well as the presence of a fibrinous exudate in the wound site, usually resulting from a traumatic insult to a vascularized tissue layer. The fibrin deposition/degradation equilibrium has emerged as a crucial factor in adhesion formation. Under continued suppressed fibrinolytic activity, the fibrin matrix begins to represent vascular granulation tissue containing cellular elements. Beginning as early as the third post-operative day, the fine threads of fibrin are invaded by fibroblasts and organized through the deposition of collagen into mature, strong, fibrous adhesions. It is clear that neighboring tissue structures will not form permanent adhesions unless they can achieve continuous, close apposition. In addition, the cellularity of the fragile fibrin matrix connecting two such structures seems to represent a critical factor in adhesion maturation. The extent of fibroblast invasion ultimately determines whether the fibrin bridge is absorbed or persists and is organized, forming an adhesion.
As mentioned already, infection may be an important complication of the wound or injury healing. Currently antibiotics and other agents are widely used for the treatment or prophylactics of infection, mostly as a powder or a spray applied over the surgical wound area before the closure. These methods of drug delivery are simple but have a disadvantage of very fast clearance of the drug from the treatment area to other areas and therefore suboptimal spatial and temporary drug concentration and distribution patterns in the cavity. There also is a wide variety of drug delivery formulations and devices suggested for the local drug delivery into the wound area. However, these products are usually preparations which are produced already containing a specific drug agent and in addition to that often contain a binding agent to contain and regulate the drug release; they are also often made of materials which do not occur naturally in a human body and have delayed or incomplete clearance from the human body when implanted. Furthermore, collagen-based drug delivery systems had been suggested with the use of liquid collagen, wherein cross linking of the liquid collagen was suggested to be performed within the body after the injection. Such a technique, however, has several disadvantages: (1) injection of a collagen form which is not naturally present in a human body; (2) injection of a cross-linking substance which is another unnatural agent; and (3) such technology is suitable for the intramural and subcutaneous delivery, but not convenient for use in surgical procedures involving body cavities and internal surgery.
There has been no report to date of a method that is unequivocally effective at preventing fibrous adhesion formation. However, numerous strategies have been evaluated in clinical settings. Such strategies include: (1) the use of biodegradable membranes or gels (also called mechanical barriers) to mechanically separate organs at the end of surgery; (2) the administration of therapeutic agents (e.g. NSAIDS, fibrinolytic agents, corticosteroids, antibiotics); and (3) performing laparoscopic (keyhole) surgery, which reduces the size of the incision and the extent to which organs are handled.
These existing methods are not without drawbacks. While select therapeutic agents have demonstrated an ability to reduce adhesion formation through their ability to alter various portions of the inflammatory wound healing response, these drugs are rapidly cleared from the wound site, which decreases their overall effectiveness during the approximately week-long fibrous adhesion formation process.
Mechanical barriers pose a potentially elegant solution to adhesion prevention. A successful barrier temporarily prevents apposition of serosal tissue surfaces by separating the adhesiogenic tissue while the normal tissue repair process occurs. Subsequent degradation and clearance of the substance from the body prevents a foreign body response involving fibrosis of the implant or local toxicity. An ideal barrier should be safe, effective, nonimmunogenic, noninflammatory, separate adhesiogenic tissue for the duration of the remesothelialization process, biodegrade, and remain functional in the presence of blood products. Further, the material should not interfere with the healing process, nor should it promote infection or abscess formation. Finally, it must inhibit the formation of adhesions while exhibiting ease of surgical use with respect to handling, application, retention at the wound site and applicability to both open and minimally invasive surgical procedures and facilitate combination with local drug application when necessary. To date the ideal barrier has yet to be developed.
A number of adhesion prevention products (mostly mechanical, biodegradable barriers) have been approved by the U.S. Food and Drug Administration (FDA) for demonstrating an ability to reduce the incidence of scarring and adhesion formation following surgery (one example, approved in 1997, is SepraFilm®, which is a synthetic biodegradable membrane). The International Adhesions Society website lists at least 12 products that have been approved by the FDA to date.
Anti-adhesion mechanical barriers that are commercially available are mostly synthetic polymeric membranes or films. Many of these products have demonstrated a degree of effectiveness but have several common drawbacks with regard to surgical use or clinical complications. SepraFilm® (carboxymethylcellulose/hyaluronic acid) has documented handling difficulty and may result in intraperitoneal abscesses due to differences in clearance of its polymeric components (i.e. fragmentation of film). Interceed® (oxidized regenerated cellulose) requires meticulous hemostasis in order to function properly and the material is prone to retention at the tissue surface. Gore-tex Surgical Membrane®. (expanded polytetrafluoroethylene) is difficult to handle during laparoscopy, does not biodegrade and may require additional surgery for removal, introducing the possibility of additional adhesion formation. The safety and efficacy of newer barrier methods including Sepracoat® (hyaluronic acid gel), ferric hyaluronate, cross-linked hyaluronic acid (Incert®), and photopolymerized hydrogels is not yet known.
While these barriers endeavor to prevent the close, continuous physical contact of adhesiogenic and neighboring serosal surfaces, they do not by their nature address the key cellular aspect of the wound response that is responsible for fibrous adhesion maturation: the migration of fibroblasts into the fibrin gel matrix and its subsequent organization into a fibrous adhesion via collagen synthesis.
Scaffolds are a relatively new class of biomaterials that are utilized widely in applications of regenerative medicine. They are highly porous, degradable macromolecular solids with specific microstructural characteristics. Following irreversible injury (injury of a severe enough nature that under normal spontaneous repair processes would result in scar, or non-physiological, tissue formation), scaffolds of highly specific structure and chemical composition have been shown to induce partial regeneration in several organs, notably skin and the peripheral nerves. Induced organ regeneration, or the recovery of physiological structure and function of non-regenerative tissues at the original site of injury (de novo synthesis) was accomplished using scaffolds that simultaneously blocked myofibroblast-generated contraction (the dominant method of spontaneous wound closure in adults) while mimicking the in vivo extracellular matrix environment (particularly the stroma) of the organ of interest.
Graft co-polymers of type I collagen and a glycosaminoglycan (chondroitin-6-sulfate) that were shown to actively block contraction in skin wounds (and induce regeneration) have structural properties that accomplish three main processes: 1) reduction of TGF-β in the wound site, leading to downregulation of fibroblast (and contractile myofibroblast) recruitment following severe injury; 2) blocking orientation of myofibroblast axes in the plane of the defect where macroscopic contraction is observed; and 3) ensuring that the scaffold's contraction blocking properties persist for the duration of the interim myofibroblast contractile response but not so long as to interfere with key regenerative processes.
Importantly, collagen-GAG copolymers are effective templates for regeneration of the dermis, peripheral nerve, and conjunctiva and show promise in cartilage repair studies. The use of these analogs of the extracellular matrix has been linked to partial regeneration of the above organs, elimination of scar tissue, and a clear ability to block the contraction of fibroblasts in the wound site. Furthermore, these matrices are widely used as substrates to probe the local environment of connective tissue cell-mediated contraction and specifically, myofibroblast-mediated contraction. These scaffolds successfully induce tissue regeneration and impart contraction-blocking activity by altering the local environment of the contractile cells (fibroblasts) responsible for tissue contraction and scar formation.